Language:

Not enough evidence to show if anti-cancer drugs before and after surgery increase survival in liver cell cancer patients

Hepatocellular carcinoma, the commonest primary cancer of the liver is the sixth most common cancer in the world. According to the World Health Organization, most cases of hepatocellular carcinoma occur in Asia and Africa, however recent reports suggest that the incidence of primary liver cancer is also increasing in several developed countries, mainly in the Unites States and Europe. In Southeast Asia and Africa, hepatocellular carcinoma is predominantly associated with hepatitis B virus infection, whereas in Western countries and Japan it is associated with infection due to hepatitis C virus.

For hepatocellular carcinoma, surgery is the main form of treatment, but it is only possible for a small proportion of those afflicted. Even after curative resection, recurrence is common and is the main cause of death. Adjuvant (that is, chemotherapy after surgery) and neo-adjuvant therapy (that is, chemotherapy before surgery) are thus attempted to try to improve outcomes.

This review sets on to determine the efficacy and adverse events of different neoadjuvant therapies (drug given before) versus adjuvant therapies (drug given after) compared to surgery alone, or surgery and placebo or supportive therapy when given to improve relapse and survival rates for operable hepatocellular carcinoma. A total of 12 randomised trials were identified, totaling 843 patients. The size of the randomised clinical trials ranged from 30 to 155 patients. Nine of the twelve trials reported no survival benefit from adjuvant therapy. Two trials reported a significant difference for survival and four studies for disease-free survival for the treatment group, but the results of one of the trials on both its groups were very poor when compared to other trials. Two of the trials that did not report any absolute survival advantage reported statistically significant differences in disease-free survival. The highest toxicity rate was in a trial using oral 1-hexylcarbamoyl 5- fluorouracil which resulted in 12 out of 38 patients being withdrawn from the trial because of adverse events.

In conclusion, this review found insufficient evidence to show that adjuvant and neo-adjuvant therapy increase survival from hepatocellular carcinoma, but there is limited evidence to suggest that neoadjuvant or adjuvant therapy may be useful for disease-free survival.

Authors' conclusions:

There is no clear evidence for efficacy of any of the adjuvant and neo-adjuvant protocols reviewed, but there is some evidence to suggest that adjuvant therapy may be beneficial offering prolonged disease-free survival. In order to detect a realistic treatment advantage, larger trials with lower risk of systematic error will have to be conducted.

Read the full abstract...

Background:

Hepatocellular carcinoma is a disease of great concern. Surgery is the treatment of choice, but there is still a high recurrence rate after resection.

Objectives:

To determine the benefits and harms of neoadjuvant and adjuvant therapies compared to surgery alone or surgery and placebo/supportive therapy after curative resection for operable hepatocellular carcinoma.

Search strategy:

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE,EMBASE, Science Citation Index Expanded, Chinese Biomedical Database, and US National Cancer Institute's Physician's Data Query Trials Database until 2005. References of the identified trials were also searched for identifying further trials.

Selection criteria:

Randomised and quasi-randomised trials that compared hepatocellular carcinoma patients who were given and not given neoadjuvant/adjuvant therapy as a supplement to curative liver resection.

Data collection and analysis:

Data were extracted independently by two authors and discrepancies resolved by consensus. The survival and disease-free survival curves were compared using their one, two, three, four, and five-year survival rates, median survival times, and the result of the significance tests (P-values).

Main results:

A total of 12 randomised trials were identified, totaling 843 patients. The size of the randomised clinical trials ranged from 30 to 155 patients. Both preoperative (neoadjuvant) and postoperative (adjuvant), systemic and locoregional (+/- embolisation), chemo- and immunotherapy interventions were tested. Treatment regimens and patients selected were not comparable, so no pooling was done. Only one regimen using preoperative transcatheter arterial chemoembolisation with doxorubicin was similar in two trials. Four of the twelve trials reported survival benefit at five years when given adjuvant or neoadjuvant therapy. Disease-free survival was reported in nine trials, and the estimated hazard ratios show that disease-free survival was significant in two trials at five years. These two trials had not shown a survival advantage, but the recurrence was significantly lower in patients given adjuvant or neoadjuvant therapy. The highest toxicity rate was in a trial using oral 1-hexylcarbamoyl 5-fluorouracil which resulted in 12 out of 38 patients being withdrawn from the trial because of adverse events.